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Florian Drey,
Yeong-Hoon Choi,
Klaus Neef,
Birgit Ewert,
Arne Tenbrock,
Philipp Treskes,
Henning Bovenschulte,
Oliver J Liakopoulos,
Meike Brenkmann, Christof Stamm,
Thorsten Wittwer,
Thorsten Wahlers
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ABSTRACT: Cardiac cell therapy with mesenchymal stem cells (MSC) represents a promising treatment approach for end-stage heart failure. However, little is known about the underlying mechanisms and the fate of the transplanted cells. The objective of the presented work is to determine the feasibility of magnetic resonance imaging and in vivo monitoring after transplantation into infarcted mouse hearts using a clinical 3.0 T MRI device.The labeling procedure of bone marrow derived MSCs with micron sized paramagnetic iron oxide particles (MPIOs) did not affect the viability of the cells and their cell type defining properties when compared to unlabeled cells. Using a clinical 3.0 T MRI scanner equipped with a dedicated small animal solenoid coil 10⁵ labeled MSCs could be detected and localized in the mouse hearts for up to four weeks after intramyocardial transplantation. Weekly ECG gated scans using T1 weighted sequences were performed and left ventricular function were assessed. Histological analysis of hearts confirmed the survival of labeled MSCs in the target area up to four weeks after transplantation. In conclusion, in vivo tracking of labeled MSCs using a clinical 3.0 T MRI scanner is feasible. In combination with assessment of heart function this technology allows the monitoring of the therapeutic efficacy of regenerative therapies in a small animal model.
Cell Transplantation 10/2012; · 5.13 Impact Factor
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ABSTRACT: The effect of mechanical preconditioning on skeletal myoblasts in engineered tissue constructs was investigated to resolve issues associated with conduction block between skeletal myoblast cells and cardiomyocytes.
Murine skeletal myoblasts were used to generate engineered tissue constructs with or without application of mechanical strain. After in vitro myotube formation, engineered tissue constructs were co-cultured for 6 days with viable embryonic heart slices. With the use of sharp electrodes, electrical coupling between engineered tissue constructs and embryonic heart slices was assessed in the presence or absence of pharmacologic agents.
The isolation and expansion procedure for skeletal myoblasts resulted in high yields of homogeneously desmin-positive (97.1% ± 0.1%) cells. Mechanical strain was exerted on myotubes within engineered tissue constructs during gelation of the matrix, generating preconditioned engineered tissue constructs. Electrical coupling between preconditioned engineered tissue constructs and embryonic heart slices was observed; however, no coupling was apparent when engineered tissue constructs were not subjected to mechanical strain. Coupling of cells from engineered tissue constructs to cells in embryonic heart slices showed slower conduction velocities than myocardial cells with the embryonic heart slices (preconditioned engineered tissue constructs vs embryonic heart slices: 0.04 ± 0.02 ms vs 0.10 ± 0.05 ms, P = .011), lower maximum stimulation frequencies (preconditioned engineered tissue constructs vs embryonic heart slices: 4.82 ± 1.42 Hz vs 10.58 ± 1.56 Hz; P = .0009), and higher sensitivities to the gap junction inhibitor (preconditioned engineered tissue constructs vs embryonic heart slices: 0.22 ± 0.07 mmol/L vs 0.93 ± 0.15 mmol/L; P = .0004).
We have generated skeletal myoblast-based transplantable grafts that electrically couple to myocardium.
The Journal of thoracic and cardiovascular surgery 09/2012; 144(5):1176-1184.e1. · 3.41 Impact Factor
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Sureshkumar Perumal Srinivasan,
Klaus Neef,
Philipp Treskes,
Oliver J Liakopoulos, Christof Stamm,
Douglas B Cowan,
Navid Madershahian,
Elmar Kuhn,
Ingo Slottosch,
Thorsten Wittwer,
Thorsten Wahlers,
Yeong-Hoon Choi
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ABSTRACT: Transplantation of skeletal myoblasts (SMs) has been investigated as a potential cardiac cell therapy approach. SM are available autologously, predetermined for muscular differentiation and resistant to ischemia. Major hurdles for their clinical application are limitations in purity and yield during cell isolation as well as the absence of gap junction expression after differentiation into myotubes. Furthermore, transplanted SMs do not functionally or electrically integrate with the host myocardium. Here, we describe an efficient method for isolating homogeneous SM populations from neonatal mice and demonstrate persistent gap junction expression in an engineered tissue. This method resulted in a yield of 1.4 × 10(8) high-purity SMs (>99% desmin positive) after 10 days in culture from 162.12 ± 11.85 mg muscle tissue. Serum starvation conditions efficiently induced differentiation into spontaneously contracting myotubes that coincided with loss of gap junction expression. For mechanical conditioning, cells were integrated into engineered tissue constructs. SMs within tissue constructs exhibited long term survival, ordered alignment, and a preserved ability to differentiate into contractile myotubes. When the tissue constructs were subjected to passive longitudinal tensile stress, the expression of gap junction and cell adherence proteins was maintained or increased throughout differentiation. Our studies demonstrate that mechanical loading of SMs may provide for improved electromechanical integration within the myocardium, which could lead to more therapeutic opportunities.
Biochemical and Biophysical Research Communications 05/2012; 422(3):462-8. · 2.48 Impact Factor
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ABSTRACT: We report a rare case of the absence of a posterior tricuspid valve leaflet. A male patient, aged 46, suffering from severe tricuspid valve regurgitation (TR) of unknown aetiology and atrial septal aneurysm was referred to our hospital for surgery. On surgical inspection, the posterior tricuspid valve leaflet and its subvalvular apparatus were completely absent and only the valve annulus was seen in the corresponding position. The anterior and septal leaflets were normal. We successfully reconstructed the tricuspid valve as follows: the head of an anterior papillary muscle was approximated to the ventricular septum (Sebening stitch). After the approximation of the centre of the tricuspid annulus of the anterior leaflet to the tricuspid annulus on the opposite side, a sizer of 29 mm in diameter was easily passed through the anterior orifice. The posterior orifice was closed with running sutures (posterior annulorrhaphy after Hetzer). Before these procedures, we attempted to reconstruct the tricuspid valve with a posterior annulorrhaphy alone; however, valve competence was insufficient. A Sebening stitch was necessary to improve the valve competence. Echocardiography showed TR grade 1 at the patient's discharge from hospital and TR grade 1 to 2 at the follow-up, 10 months after the operation.
Interactive cardiovascular and thoracic surgery 03/2012; 14(6):883-5.
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ABSTRACT: In the past, cell transplantation strategies for the treatment of heart failure have shown promising results in experimental and clinical studies. Bone marrow (BM)-derived stem cells represent the most frequently used cell population. Within this heterogeneous cell population, mesenchymal stromal cells (MSC) have been identified to induce therapeutic effects, mainly through paracrine mechanisms. Because of their low frequency in native tissues, in vitro cell culture expansion is mandatory prior to transplantation. We sought to identify patient-specific cardiovascular risk factors influencing the proliferative potential of MSC.
BM aspirates from 51 patients undergoing elective cardiac surgery were analyzed for MSC frequency and cell culture expansion potential. Fibroblastic colony-forming units (CFU-F) were quantified for culture conditions applying autologous (AS) or fetal bovine serum (FBS) and different basic media. Univariate and multivariate analyzes were performed in order to determine the impact of patient-specific factors on CFU-F numbers.
Expanded MSC showed a specific immune phenotype and displayed adipogenic, chondrogeneic and osteogeneic differentiation potential. CFU-F numbers did not differ under AS or FBS supplementation. Elevated numbers of mononuclear cells, diabetes mellitus, steroid treatment, chronic obstructive pulmonary disease, renal failure, high euroSCORE and impaired left ventricular function were significant determinants for higher CFU-F numbers.
The impact of specific cardiovascular risk factors on MSC fitness could be determined. These results may help to establish patient profiling in order to identify patients suitable for autologous MSC transplantation, and might lead to the identification of disease-related mechanisms of stem cell activation.
Cytotherapy 03/2012; 14(6):670-8. · 3.63 Impact Factor
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The Lancet 03/2012; 379(9819):891; author reply 891-2. · 38.28 Impact Factor
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ABSTRACT: More than 10 years ago, the first clinical application of cardiac cell therapy was performed in a patient undergoing coronary bypass grafting (CABG). Ever since, catheter-based cell delivery approaches have dominated the field, but surgical cell therapy continues to provide important information on safety and efficacy of various cell therapy strategies. The open chest offers unrivalled simplicity and precision of intramyocardial cell injection, and the cardiac surgical patient population includes those with very advanced heart disease who are in greatest need of innovative regeneration concepts. In this review, the clinical experience with cardiac surgical cell therapy is summarized and critically appraised.
Current pharmaceutical design 09/2011; 17(30):3348-55. · 4.41 Impact Factor
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ABSTRACT: We aimed to evaluate the adaptive growth and remodeling behavior of the transplanted heart in pediatric heart-transplant recipients by comparing donor body surface area (BSA) and cardiac dimensions during transplantation with the corresponding parameters of the recipient over a period of time.
A retrospective review of medical and echocardiographic records of 167 children (8.65 ± 5.98, median 9; range 0-17 years) who underwent orthotopic heart transplantation between 1987 and March 2010 was done.
In the first 30 days post-transplantation, right- and left-ventricular end-diastolic diameters, volumes, and myocardial mass were found to be significantly increased (z score 3.96, p < 0.000) in relation to the recipients' BSA. Within the first year of post-transplantation, there was a significant reduction in the right-ventricular diameter (z score, -1.0 to +1.6, p = 0.000), left-ventricular diameter (z score -1.0 to +1.9, p = 0.000), right-ventricular end-diastolic volume (z score -1.3 to +1.9, p = 0.000) and left-ventricular end-diastolic volume (z score -1.3 to +1.8, p = 0.000), right-ventricular mass (z score, -1.4 to +1.7, p = 0.000) and left-ventricular mass (z score, -1.4 to +1.8, p = 0.000). During subsequent follow-up periods of 2-5 and 6-10 years, the aforementioned cardiac dimensions and volumes increased appropriately in accordance to the BSA (p = 0.000). In all the cardiac dimensions and volumes measured, donor-recipient mismatch did not influence the continuous growth of the measured parameters, which was in accordance to the recipients' BSA over time. Kaplan-Meier survival analysis showed a survival rate of 61.7% at 10 years. There is no statistically significant difference in survival rate among patients with varying donor-recipient weight ratios and donor-recipient BSA ratios (p = 0.53).
This study demonstrates that the transplanted heart undergoes remodeling processes and grows adaptively, in accordance to the BSA, over a period of time.
European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 09/2011; 40(6):1374-82; discussion 1382-3. · 2.40 Impact Factor
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ABSTRACT: Our objective was to elucidate long-term clinical and functional effects of intramyocardial stem cell transplant and to identify patients who will show sustained benefit.
Long-term outcomes of 35 patients after intramyocardial CD133(+) bone marrow stem cell transplant during coronary artery bypass grafting were compared with those of a control group of 20 patients after coronary artery bypass grafting alone. Clinical effects were assessed with the New York Heart Association classification system and the Minnesota Living With Heart Failure questionnaire. Electrocardiography, 24-hour Holter monitoring, echocardiography, myocardial perfusion scanning, magnetic resonance imaging, and computed tomography were performed. Logistic regression analyses were used to identify prognostic factors for improvement in long-term left ventricular ejection fraction after stem cell treatment.
The stem cell group revealed similar New York Heart Association and life quality scores to the control group. Myocardial perfusion score at the area of risk was significantly increased in the stem cell group after 36-month follow-up (P = .024 vs control). Multivariate logistic regression analysis revealed a 44-fold higher probability of at least 5% improvement in left ventricular ejection fraction for patients with preoperative left ventricular ejection fraction not greater than 40% than for patients with preoperative ejection fraction greater than 40% (P = .018). Furthermore, patients operated on between 7 and 12 weeks after myocardial infarction had a 56-fold higher chance of at least 5% improvement in left ventricular ejection fraction than patients treated later than 12 weeks after infarction (P = .023).
Intramyocardial stem cell therapy was safe but lacked significant lasting benefits beyond 6 months in our study cohort with a limited number of patients. Preoperative left ventricular ejection fraction and time since myocardial infarction may be critical parameters for selection of patients who can benefit most from intramyocardial stem cell treatment during coronary artery bypass grafting.
The Journal of thoracic and cardiovascular surgery 06/2011; 142(6):1530-9.e3. · 3.41 Impact Factor
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ABSTRACT: Septal myectomy is the treatment of choice for patients with hypertrophic obstructive cardiomyopathy (HOCM) with significant left-ventricular outflow tract (LVOT) obstruction. In some HOCM patients, however, systolic anterior motion (SAM) of the anterior mitral leaflet significantly contributes to LVOT obstruction, resulting in mitral regurgitation and insufficient release of the obstruction after myectomy. We, therefore, developed a strategy of combined myectomy and anterior leaflet retention plasty (ALRP), and investigated its results in adult HOCM patients with manifest SAM.
Subaortic septal myectomy and ALRP were performed in 25 adult HOCM patients with significant SAM, as assessed by echocardiography (mean age = 48.5 ± 15 years). All patients received cardiac catheterization and echocardiography evaluation prior to the operation, before discharge, and at follow-up. Follow-up ranged between 0.8 and 14 years (median = 2.5 years).
All patients survived the operation, and the Kaplan-Meier estimated survival was 100% at 1 year and 82 ± 6% at 5 years. Freedom from re-operation at 5 years was 83 ± 8%. The mean LVOT pressure gradient decreased from 84 ± 32 to 19 ± 11 mm Hg postoperatively (p < 0.001), and only two patients had mild residual or recurrent SAM at follow-up. Mitral regurgitation and New York Heart Association classification were also markedly improved at follow-up.
Combined subaortic septal myectomy and ALRP is a safe and effective therapy in HOCM patients with significant SAM. ALRP can help prevent residual or recurrent LVOT obstruction and improves mitral regurgitation.
European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 05/2011; 40(6):1515-20. · 2.40 Impact Factor
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ABSTRACT: Negative pressure wound therapy is the first-line treatment modality for poststernotomy mediastinitis in many heart centers. The aim of this study was to analyze major complications and possible preventive methods during negative pressure wound therapy in patients with deep sternal wound infections.
We retrospectively analyzed 69 consecutive patients treated with negative pressure wound therapy for poststernotomy mediastinitis between June 2006 and September 2009.
Five (7.2%) patients sustained major complications during negative pressure wound therapy. Bleeding from coronary artery venous bypass grafts was observed in 4 patients and fulminant bleeding from an infected homograft of the ascending aorta was observed in 1 patient during routine dressing changes of the negative pressure wound therapy system.
Bleeding is the major complication during negative pressure wound therapy for poststernotomy mediastinitis. Covering the heart with several layers of paraffin gauze is a necessary protective maneuver but cannot completely prevent major complications during negative pressure wound therapy. All operative procedures, including dressing changes, should be performed in the operating room under optimal hygienic and monitoring conditions to increase the salvage rate and to guarantee optimal surgical and anesthesiologic conditions in case of negative pressure wound therapy-related complications.
The Journal of thoracic and cardiovascular surgery 11/2010; 140(5):1133-6. · 3.41 Impact Factor
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ABSTRACT: Despite refinements of medical and surgical therapies, heart failure remains a fatal disease. Myocardial infarction is the most common cause of heart failure, and only palliative measures are available to relieve symptoms and prolong the patient's life span. Because mammalian cardiomyocytes irreversibly exit the cell cycle at about the time of birth, the heart has traditionally been considered to lack any regenerative capacity. This paradigm, however, is currently shifting, and the cellular composition of the myocardium is being targeted by various regeneration strategies. Adult progenitor and stem cell treatment of diseased human myocardium has been carried out for more than 10 years (Menasche et al., 2001; Stamm et al., 2003), and it has become clear that, in humans, the regenerative capacity of hematopoietic stem cells and endothelial progenitor cells, despite potent proangiogenic effects, is limited (Stamm et al., 2009). More recently, mesenchymal stem cells (MSCs) and related cell types are being evaluated in preclinical models of heart disease as well as in clinical trials (see Published Clinical Trials, below). MSCs have the capacity to self-renew and to differentiate into lineages that normally originate from the embryonic mesenchyme (connective tissues, blood vessels, blood-related organs) (Caplan, 1991; Prockop, 1997; Pittenger et al., 1999). The current definition of MSCs includes plastic adherence in cell culture, specific surface antigen expression (CD105(+)/CD90(+)/CD73(+), CD34(-)/CD45(-)/CD11b(-) or CD14(-)/CD19(-) or CD79α(-)/HLA-DR1(-)), and multilineage in vitro differentiation potential (osteogenic, chondrogenic, and adipogenic) (Dominici et al., 2006 ). If those criteria are not met completely, the term "mesenchymal stromal cells" should be used for marrow-derived adherent cells, or other terms for MSC-like cells of different origin. For the purpose of this review, MSCs and related cells are discussed in general, and cell type-specific properties are indicated when appropriate. We first summarize the preclinical data on MSCs in models of heart disease, and then appraise the clinical experience with MSCs for cardiac cell therapy.
Human gene therapy 11/2010; 22(1):3-17. · 4.20 Impact Factor
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ABSTRACT: Although significant advances have been made in terms of pharmacological, catheter-based, and surgical palliation, heart failure remains a fatal disease. As a curative concept, regenerative medicine aims at the restoration of the physiologic cellular composition of diseased organs. So far, clinical cardiac regeneration attempts have only been moderately successful, but a better understanding of myocardial cell homeostasis and somatic as well as embryonic stem cell biology has opened the door for the development of more potent therapeutic cardiac regeneration strategies. Accumulating evidence indicates that the postnatal mammalian heart retains a pool of tissue-specific progenitor cells and is also repopulated by cells from extracardiac sources. However, this intrinsic myocardial regeneration potential clearly needs to be augmented by either manipulation of the cell cycle of differentiated cells, activation of resident cardiac progenitor cells, and/or the transplantation of exogenous cells. This review summarizes the recent developments in cardiac regenerative medicine, many of which may find their way into the clinical setting in the foreseeable future.
Cardiovascular Therapeutics 10/2010; 29(1):2-16. · 2.35 Impact Factor
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ABSTRACT: Left ventricular (LV) mechanical circulatory support (MCS) may be necessary after repair of anomalous left coronary artery from the pulmonary artery. We evaluated LV function parameters for their ability to predict postoperative need for MCS.
Fourteen infants (median age, 3.6; range, 2.3 to 12 months) underwent direct aortic reimplantation of the left coronary artery. We compared preoperative LV end-diastolic diameter, end-diastolic pressure, ejection fraction, and fraction of shortening of 8 patients with successful weaning from cardiopulmonary bypass (group 1) and 6 patients with unsuccessful weaning from cardiopulmonary bypass and temporary MCS support (group 2).
No perioperative or late deaths occurred. All patients at follow-up were free of reoperation (median follow-up, 10.4 years [range, 1.4 to 17 years]). Median preoperative LV end-diastolic diameter (47 [range, 41 to 60 mm] vs 32 mm [range, 21 to 36 mm]) and LV end-diastolic pressure (20 [range, 18 to 25 mm Hg] vs 12 mm Hg [range, 7 to 20 mm Hg]) were significantly higher in group 2 than in group 1 (p = 0.002 and p = 0.048). LV ejection fraction (0.28 [range, 0.19 to 0.37] vs 0.43 [range, 0.23 to 0.76]) and LV fraction of shortening (9% [range, 7% to 15%] vs 22% [range 13% to 30%]) were significantly lower in group 2 than in group 1 (p = 0.035 and p = 0.002). MCS support duration ranged from 4 to 12 days. There were no significant differences in LV function parameters at discharge or during follow-up between the groups.
A preoperative LV end-diastolic diameter above 40 mm is the strongest predictor for postoperative temporary MCS after anomalous left coronary artery from the pulmonary artery repair in infancy. However, even with temporary MCS, direct aortic reimplantation for anomalous left coronary artery from the pulmonary artery can be performed with no mortality and excellent LV recovery.
The Annals of thoracic surgery 08/2010; 90(2):580-7. · 3.74 Impact Factor
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ABSTRACT: Negative pressure wound therapy (NPWT) is a recently introduced treatment modality for post-sternotomy mediastinitis. The aim of this study was to compare the mortality rate, the sternal re-infection rate and the length of hospital stay in patients with post-sternotomy mediastinitis after NPWT and conventional treatment.
We retrospectively analysed 118 patients with post-sternotomy mediastinitis after cardiac surgery. One group of 69 patients was treated with NPWT and the other group of 49 patients with conventional therapy.
There were no major differences between the two groups concerning preoperative data (EuroScore) or primary cardiac surgery (mainly coronary artery bypass grafting). NPWT therapy was found to reduce mortality rate (P=0.005) and sternal re-infection rate (P=0.008) compared with conventional treatment and tended to lead to a shorter length of hospital stay (P=0.08).
NPWT for post-sternotomy mediastinitis demonstrates encouraging clinical results with a reduction of the mortality rate and the sternal re-infection rate compared with conventional treatment. The results support NPWT as the first-line treatment for deep sternal wound infections.
European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 02/2010; 38(1):110-3. · 2.40 Impact Factor
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ABSTRACT: Regenerative medicine encompasses "tissue engineering" - the in vitro fabrication of tissues and/or organs using scaffold material and viable cells - and "cell therapy" - the transplantation or manipulation of cells in diseased tissue in vivo. In the cardiovascular system, tissue engineering strategies are being pursued for the development of viable replacement blood vessels, heart valves, patch material, cardiac pacemakers and contractile myocardium. Anecdotal clinical applications of such vessels, valves and patches have been described, but information on systematic studies of the performance of such implants is not available, yet. Cell therapy for cardiovascular regeneration, however, has been performed in large series of patients, and numerous clinical studies have produced sometimes conflicting results. The purpose of this chapter is to summarize the clinical experience with cell therapy for diseases of the cardiovascular system, and to analyse possible factors that may influence its outcome.
Advances in biochemical engineering/biotechnology 01/2010; 123:293-317. · 1.64 Impact Factor
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ABSTRACT: The number of circulating endothelial progenitor cells (EPC) depends on cytokine release and is also associated with cardiovascular risk factors. During cardiopulmonary bypass (CPB) the endothelium is the first organ to be affected by mechanical and immunologic stimuli. We hypothesized that the magnitude of EPC mobilization by CPB correlates with the pre-operative cardiovascular morbidity profile.
EPC were quantified in blood samples from 30 patients who underwent cardiac surgery by magnetic bead isolation and fluorescence-activated cell sorting (FACS) analysis, based on concomitant expression of CD34, CD133 and CD309. Patients were divided into two groups based on the European System for Cardiac Operative Risk Evaluation (EuroSCORE): low risk (LR) and high risk (HR). Ten healthy volunteers served as controls. Samples were obtained before the start of CPB and at 1 and 24 h post-operatively. Plasma samples were collected for determination of release levels of cytokines and growth factors.
All CPB patients showed a significantly reduced basal number of EPC compared with healthy individuals (LR 5.60 +/- 0.39/mL, HR 3.89 +/- 0.34/ mL, versus control 0.807 +/- 0.82/mL, P = 0.012 versus LR, P< 0.001 versus HR). CPB induced EPC release that peaked 1 h after surgery (pre-operative 4.79 +/- 0.32/mL, 1 h 57.49 +/- 5.31/mL, 24 h 6.67 +/- 1.05/mL, P< 0.001 pre-operative versus 1 h, P< 0.001 pre-operative versus 24 h) and was associated with the duration of CPB. However, EPC release was significantly attenuated in HR patients (33.09 +/- 3.58/mL versus 81.89 +/- 4.36/mL at 1 h after CPB, P < 0.0001) and inversely correlated with the pre-operative EuroSCORE. Serum granulocyte-colony-stimulating factor (G-CSF), stem cell factor (SCF) and vascular endothelial growth factor (VEGF) levels increased throughout the observation period and were also correlated with the EPC count.
Cardiovascular risk factors influence the mobilization of EPC from the bone marrow after stimulation by CPB. This could be secondary to impaired mobilization or the result of increased EPC turnover, and may have implications for future cell therapy strategies in cardiac surgical patients.
Cytotherapy 11/2009; 12(1):79-87. · 3.63 Impact Factor
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ABSTRACT: Calcium sensitising inotropes are increasingly being used in cardiac surgical patients. Theoretically, increasing contractile protein sensitivity to Ca(2+) prevents the Ca(2+) elevation associated arrhythmogenicity and potentiates the inotropic effect of catecholamines. On the other hand, we hypothesised that Ca(2+) sensitisation exacerbates post-ischaemic myocardial stunning by impairing diastolic relaxation, which might have deleterious effects in postoperative cardiac surgical patients.
In an isolated rabbit heart model, 45 min normothermic ischaemia with potassium-induced cardioplegic arrest was followed by 120 min reperfusion. Isovolumetric left ventricular (LV) function and myocardial oxygen consumption (MvO(2)) were measured, and cytosolic Ca(2+) was monitored by rhod-2 surface spectrofluorometry. During reperfusion, ORG 30029 (250 microM) and levosimendan (0.5 microM) were used as Ca(2+) sensitisers (ORG, n=6, Levo, n=6), Ca(2+) de-sensitisation was induced with butanedione-monoxime (5mM, BDM, n=6), and dopamine (20 nM) served as a representative catecholamine (n=6). To counteract the PDE III inhibiting properties of ORG and Levo, IGF-1 (0.1 microM) and parathyroid hormone (0.05 microM) were used.
As expected, ischaemia/reperfusion induced moderate cytosolic calcium overload. Dopamine increased LV contractility and MvO(2) by augmenting the amplitude of the Ca(2+) transient, but relaxation was unchanged due to faster diastolic Ca(2+) removal. Dopamine-induced Ca(2+) handling was unchanged after uncoupling the Mg-ATPase with BDM, and MvO2 decreased in proportion with the reduced LV mechanical work load. ORG improved contractility without apparent effects on Ca(2+) handling, and MvO(2) remained constant despite increased contractile work. Conversely, ORG induced a rightward shift of the diastolic pressure-volume relationship in post-ischaemic hearts (diastolic pressure at 0.8 ml balloon volume 14.3+/-5 mmHg, p=0.01 vs control), but not in non-ischaemic control hearts. With levosimendan, the Ca(2+) sensitising effects were less pronounced (7.6+/-3 mmHg, p=0.4 vs control). By counteracting the PDE inhibiting effects of ORG and Levo using parathyroid hormone and IGF-1, the negative lusotropic effects of Ca(2+) sensitisation were unmasked.
Calcium sensitisation improves systolic function and energetic efficiency. However, Ca(2+) sensitisers should be used with caution during post-ischaemic reperfusion, as they may exacerbate myocardial stunning and thus impair cardiac output.
European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 08/2009; 37(2):376-83. · 2.40 Impact Factor
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ABSTRACT: Abnormal hemodynamic loading often accompanies congenital heart disease both before and after surgical repair. Adaptive and maladaptive myocardial responses to increased load are numerous. This study examined the hypothesis that myocyte loss occurs during compensatory hypertrophic growth in the developing infant myocardium subjected to progressive pressure overload.
Pressure-overload left ventricular hypertrophy was induced in 7- to 10-day-old rabbits by banding the thoracic aorta. Left ventricular function and mechanics were quantified by serial echocardiography and noninvasive left ventricular wall stress analysis. Left ventricular tissue sections were examined for fibrosis by using Masson's trichrome stain and for myocyte apoptosis by using a myocyte-specific DNA fragmentation assay and caspase-3 activation (specific fluorescent substrate).
Significant myocyte apoptosis (198 +/- 37/10(6) myocytes, P < .01 vs control) and caspase-3 activation were present in early hypertrophy when left ventricular contractility was preserved and compensatory hypertrophy had normalized wall stress. By 6 weeks, multiple indices of left ventricular contractility were reduced, and left ventricular wall stress was increased. Myocyte apoptosis was accelerated (361 +/- 56/10(6) myocytes), caspase-3 activity further increased, and the estimated total number of left ventricular myocytes was significantly reduced by 18% +/- 4%.
In experimental infant left ventricular hypertrophy, myocyte apoptosis is initiated in the face of normalized wall stress and preserved contractility. The ongoing rate of apoptosis causes a measurable decrease in myocyte number that is coincident with the onset of ventricular dysfunction. It thus appears that pressure overload, even at its earliest stages, is not well tolerated by the developing ventricle.
The Journal of thoracic and cardiovascular surgery 06/2009; 137(6):1356-62, 1362.e1-3. · 3.41 Impact Factor
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ABSTRACT: Influencing cellular regeneration processes in the heart has been a long-standing goal in cardiovascular medicine. To some extent, this has been successful in terms of vascular regeneration as well as intercellular connective tissue remodeling processes. Several components of today's routine heart failure medication influence endothelial progenitor cell behavior and support collateral vessel growth in the heart, or have been shown to prevent or reverse fibrosis processes. Cardiomyocyte regeneration, however, has so far escaped therapeutic manipulation strategies. Delivery of exogenous cells of bone marrow origin to the human myocardium may improve heart function, but is not associated with relevant neomyogenesis. However, accumulating evidence indicates that the myocardium contains resident cardiac progenitor cells (CPC) that may be therapeutically useful. This notion indeed represents a paradigm shift but is still controversial. The purpose of this review is to summarize the rapidly expanding current knowledge on CPC, and to assess whether it may be translated into solid therapeutic concepts.
Therapeutic Advances in Cardiovascular Disease 06/2009; 3(3):215-29.
